Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

L-DOPA-induced dyskinesias (LIDs) are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs

Etude in vivo du contrôle inhibiteur tonique et phasique exercé par les récepteurs sérotoninergiques de type 5-HT2c sur l'activité des voies dopaminergiques nigrostriée et mésoaccumbale chez le rat

Ce travail, portant sur le récepteur sérotoninergique 2C (5-HT2c), a eu pour but d'approfondir la nature du contrôle tonique et phasique inhibiteur exercé par ce récepteur sur la libération de DA mesurée par microdyalyse intracérébrale dans le noyau accumbens (NAc) et le striatum chez le rat anestrhésié à l'halothane. A l'aide d'outils pharmacologiques appropriés (agoniste, agoniste inverse et antagoniste des récepteurs 5-HT2c), nous avons évalué 1) la participation de l'activité constitutive des récepteurs 5-HT2c in vivo 2) l'importance du niveau d'activité des neurones DA ascendants, et 3) l'existence de contrôles région-dépendants sur la voie DA mésolimbique. Dans les deux régions d'intérêt, l'effet excitateur de l'agoniste inverse 5 HT2c le SB 206553 sur la libération de DA est bloqué par l'antagoniste 5-HT2c le SB 242084 mais pas modifié par une réduction du tonus 5-HT central. Le SB 206553, sans effet sur la libération de DA induite par la clozapine, potentialise celle induite par l'halopéridol, alors que le SB 242084, sans effet sur l'halopéridol, bloque de façon dose-dépendante l'effet de la clozapine. Ces deux ligands 5-HT2c potentialisent la libération de DA évoquée par la cocaine alors que l'agoniste 5-HT2c le Ro 60-0175 ne la modifie pas, mais réduit celle induite par l'halopéridol. Enfin, l'application locale d'antagonistes 5-HT2c dans l'aire tegmentale ventrale (ATV) et le NAc bloque la diminution de la libération accumbale de DA induite par l'administration systémique du Ro 60-0175. Nos données montrent que 1) l'activité constitutive des récepteurs 5-HT2c participe au contrôle tonique inhibiteur exercé sur les neurones DA mésoaccumbaux et nigrostriés in vivo en conditions basales et activées ; 2) les récepteurs 5-HT2c modulent l'exocytose de DA de façon dépendante du degré d'activation des neurones DA ; 3) le contrôle inhibiteur de la voie DA mésolimbique implique, au moins en partie, les récepteurs 5-HT2c de l'ATV et du NAc. Ce travail ouvre des perspectives tant physiologiques que thérapeutiques quant au rôle des récepteurs 5-HT2c au sein des ganglions de la base.This study, concerning the serotonergic 2C (5-HT2c) receptor, was aimed to go deeper into the mechanisms of the tonic and phasic inhibitory control exerted by this receptor on DA release measured by intracerebral microdialysis in the halothane-anesthetized rat nucleus accumbens (NAc) and striatum. By using appropriate pharmacological tools (agonist, inverse agonist, antagonist of 5-HT2c receptors), we explored 1) the participation of the constitutive activity of 5-HT2c receptors in vivo 2) the relevance of the degree of activity of mesolimbic and nigrostriatal DA neurons, and 3) the existence of region-dependant controls of the mesolimbic DA pathway. In both brain regions, the excitatory effect of the 5-HT2c inverse agonist SB 206553 on DA release is blocked by the 5-HT2c antahonist SB 242084 but not modified by the reduction of the central 5-HT tone. SB 206553, without effect on clozapine-stimulated DA release, potentiates haloperidol-induced DA release, whereas SB 242084, without effect on haloperidol, dose-dependently blocks the DA effect of clozapine. Both 5-HT2c ligands potentiate cocaine-stimulated DA release while the 5-HT2c agonist Ro 60-0175 does not affect the DA effect of cocaine but reduces that of haloperidol. Finally, the local application of 5-HT2c antagonists in the ventral tegmental area (VTA) and the NAc blocks the inhibition of accumbal DA release induced by the systemic administration of Ro 60-0175. These findings show that 1) the constititive activity of 5-HT2c receptors participates in the tonic inhibitory control of mesoaccumbal and nigrostriatal DA neurons in vivo ; 2) 5-HT2c receptors modulate DA exocytosis in a manner that is dependent of the degree of activation of ascending DA neurons ; 3) the 5-HT2c-dependent inhibitory control of the mesolimbic DA pathway is mediated, at least in part, by 5-HT2c receptors located in the VTA and the NAc. This work brings up new physiological and therapeutical perspectivesconcerning the role of 5-HT2c receptors in the basal ganglia.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Expression of Glucocorticoid Receptor and Early Growth Response Gene 1 during Postnatal Development of Two Inbred Strains of Mice Exposed to Early Life Stress

Early life stress can elicit profound changes in adult gene expression and behavior. One consequence of early life stress is a decreased expression of glucocorticoid receptors (GRs) in the frontal cortex and hippocampus. However, neither the time of onset nor the mechanism(s) leading to decreased GR expression during postnatal development are known. The present study used two inbred strains of mice that differ in their behavioral responsiveness to stress (Balb/c and C57Bl/6), exposed them to an established paradigm of early life stress (infant maternal separation), and measured their expression of frontal cortical and hippocampal GRs and the putative transcriptional activator of the GR gene, early growth response gene (egr)-1, at defined stages of postnatal development. In both strains, real-time RT-PCR experiments revealed that decreased expression of GR in adolescence and adulthood is, in fact, preceded by increased GR expression during early life stress exposure. Thus, the early life stress-induced disruption of the normal stress-hyporesponsive period during infancy is accompanied by increased GR expression. Moreover, chronic treatment with the antidepressant drug fluoxetine during adolescence or adulthood reversed the effect of early life stress on adult GR mRNA expression. In contrast to the strain-independent effect of early life stress on GR expression, however, changes in egr-1 expression occurred only in Balb/c mice, and unlike the biphasic developmental changes in GR mRNA expression, egr-1 mRNA was decreased throughout postnatal development. Moreover, there was no consistent overlap of anatomic regions affected by decreased GR and egr-1 protein expression. Thus, in Balb/c mice, changes in GR and egr-1 expression can independently contribute to the phenotypes resulting from early life stress exposure. These findings illustrate that the impact of early life stress on gene expression changes is modulated by the genetic background and that the persistent changes in GR and egr-1 expression that arise early during postnatal developmental are reversible by chronic fluoxetine treatment during adolescence and adulthood

Coordinated Recruitment of Cortical–Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats

International audiencePeople with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical–striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking

Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson's disease.

International audienceThe therapeutic benefit of L-DOPA is commonly attributed to restoration of dopamine (DA) extracellular levels in the striatum of Parkinsonian patients. However, the loss of efficacy of L-DOPA after chronic use is paradoxically associated with a similar or enhanced striatal DA response. Release of L-DOPA-derived DA depends on the widespread serotonergic (5-HT) innervation in the brain. Chronic exposure of 5-HT neurons to L-DOPA could lead to aberrant neurochemical responses beyond the striatum. Using multi-site intracerebral microdialysis in a rat model of Parkinson's disease, we showed that chronic L-DOPA treatment at a therapeutic dose (12 mg/kg/day for 10 days) homogeneously reduced basal 5-HT release and metabolism. These effects were paralleled by a decrease in tissue content of 5-HT and its metabolite. Chronic L-DOPA treatment severely altered the brain pattern of 5-HT and DA release responses to L-DOPA (3-12 mg/kg) with an overall loss of efficacy of L-DOPA to increase DA release. Our data demonstrate for the first time in vivo that the impairment of 5-HT neuronal function induced by chronic L-DOPA alters in a region-dependent manner L-DOPA-induced DA release. Changes in neurochemical pattern of L-DOPA in the brain may favour the occurrence of both motor and non-motor side effects

Discriminative inhibitory control of cocaine seeking involves the prelimbic prefrontal cortex.

International audienceBACKGROUND:Recent neuroimaging studies have shown that people with cocaine addiction retain some degree of control over drug craving that correlates with neural activity in the lateral prefrontal cortex (PFC). Here, we report similar findings in a rat model of inhibitory control of cocaine seeking.METHODS:Rats actively responding for cocaine were trained to stop responding when presented with a discriminative stimulus that signaled lack of reinforcement. Rats were then tested for inhibitory control of cocaine seeking in novel behavioral contexts and in circumstances when cocaine seeking is particularly intense (e.g., following drug priming). The role of neuronal activity in different subregions of the PFC was assessed using local pharmacologic inactivation and c-Fos immunohistochemistry.RESULTS:Rats progressively acquired the ability to stop cocaine seeking, even during drug intoxication and after a long history of cocaine self-administration. Inhibitory control of cocaine seeking was flexible, sufficiently strong to block cocaine-primed reinstatement, and selectively depended on increased neuronal activity within the prelimbic PFC, which is considered the rodent functional homolog of the human lateral PFC.CONCLUSIONS:Parallel evidence in both animal models and humans indicate that recruitment of prefrontal inhibitory control of drug seeking is still functional after prolonged cocaine use. Preclinical investigation of the mechanisms underlying this capacity may contribute to designing new behavioral and/or pharmacologic strategies to promote its use for the prevention of relapse in addiction

Large-scale brain correlates of sweet versus cocaine reward in rats

Cocaine induces many supranormal changes in neuronal activity in the brain, notably in learning- and reward-related regions, in comparison to nondrug rewards - a difference that is thought to contribute to its relatively high addictive potential. However, when facing a choice between cocaine and a nondrug reward (e.g., water sweetened with saccharin), most rats do not choose cocaine, as one would expect from the extent and magnitude of its global activation of the brain, but instead choose the nondrug option. We recently showed that cocaine, though larger in magnitude, is also an inherently more delayed reward than sweet water, thereby explaining why it has less value during choice and why rats opt for the more immediate nondrug option. Here we used a large-scale fos brain mapping approach to measure brain responses to each option in saccharin-preferring rats, with the hope to identify brain regions whose activity may explain the preference for the nondrug option. In total, fos expression was measured in 142 brain levels corresponding to 52 brain subregions and composing 5 brain macrosystems. Overall, our findings confirm in rats with a preference for saccharin that cocaine induces more global brain activation than the preferred nondrug option does. Only very few brain regions were uniquely activated by saccharin. They included regions involved in taste processing (i.e., anterior gustatory cortex) and also regions involved in processing reward delay and intertemporal choice (i.e., some components of the septohippocampal system and its connections with the lateral habenula)

Relapse to cocaine use persists following extinction of drug-primed craving

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